TRPC6 inhibition in FSGS: a phase 2 trial of BI 764198

Focal segmental glomerulosclerosis (FSGS) is a glomerulopathy arising from a range of pathological insults that result in podocyte loss and progressive kidney function decline. Despite improvements in prognosis over time, the adverse outcomes of FSGS on kidney survival remain severe, especially in those with steroid resistant disease, underscoring the urgent need to develop safe and effective therapies. 

Altered activity of transient receptor potential cation channel, subfamily C, member 6 (TRPC6) in podocytes has been implicated in the initiation and progression of FSGS. Modulation of TRPC6 might, therefore, offer a novel mechanism to preserve podocyte function and survival. Phase 1 studies have suggested that BI 764198, a novel, potent, selective TRPC6 inhibitor, is well tolerated when administered once daily in single and multiple rising doses for up to 14 days.

In a multicentre, randomised, double-blind, placebo-controlled phase 2 trial, Trachtman and colleagues assessed the safety and efficacy of BI 764198 in adults with biopsy-confirmed FSGS or FSGS caused by known variants of the TRPC6 gene. Participants were allocated in a 1:1:1:1 ratio to receive one of three oral doses of BI 764198 (20 mg, 40 mg or 80 mg) once daily or to matched placebo over 12 weeks. Eligibility criteria included urine protein–creatinine ratio (UPCR) of ≥1.0 g/g and eGFR of ≥30 mL/min/1.73 m².  The trial included participants who were steroid-naïve and those who had been treated with or were currently on corticosteroids.

A total of 62 individuals received treatment, although two with missing data were excluded from the full analysis. Overall, 37 participants (60%) were male, mean age was 40.7 years and 39 (63%) were of White ethnicity. 

The primary endpoint was a ≥25% reduction in UPCR from baseline at week 12. This response was observed in 8 (44%) of 18, 2 (14%) of 14 and 6 (43%) of 14 participants receiving BI 764198 20 mg, 40 mg and 80 mg, respectively (corresponding to 16 [35%] of 46 for all dose groups). In comparison, only 1 (7%) of 14 receiving placebo met this endpoint. The corresponding odds ratios versus placebo were 10.0 (95% CI, 1.6–118.1), 1.5 (0.2–19.5) and 6.0 (0.9–73.6) for the three BI 764198 doses, and 4.9 (1.0–48.8) for all dose groups.

Notably, the reduction in proteinuria was consistent among individuals with FSGS resulting from TRPC6 variants.

BI 764198 was well tolerated, with a similar incidence of adverse events in the treatment arms (34 [71%] of 48) compared with placebo (10 [71%] o f14). However, the safety profile needs to be confirmed with more extended use of the drug.  

These findings provide the first evidence supporting the efficacy of a podocyte-targeted therapy in FSGS and justify proceeding to a phase 3 trial in a comparable population to assess longer-term clinical outcomes in a larger cohort.

The full article can be read here.